Disease/Drug of interest: Rabies/Ribavirin Motivation and Background: Rabies is one of the most ancient known neurological diseases. The disease has been known for over 4000 years, but it was fatal with no treatment for most of that time. It was not until 1885 that the first vaccine for rabies was discovered. Rabies, although rare in the United States, account for about 55,000 deaths annually. Of the deaths, 1-3 of the cases are reported in the United States while the majority of the cases are from developing countries [6]. Rabies is a deadly virus that is contracted by humans through the bite of a mammal. In the United States, the most common transmitters of rabies are bats, coyotes, foxes, raccoons, and skunks [6]. Once the virus enters from the bite mark, the virus first interacts with the muscle cells. The virus replicates slowly and quietly while in the muscle cells so that the immune system does not attack the virus. After replicating in the muscle cells, the virus targets the phosphoprotein which decreases the gene that helps fight infectious diseases [2]. The ultimate effect of rabies is inflammation of the brain after an attack on the central nervous system. A rabies shot can be taken after an animal bite to try to prevent a rabies infection, but once the symptoms are present, other options must be considered. If no treatments are taken after these symptoms appear, the disease is fatal within days [6]. Although there are not many cases of rabies in the United States, 55,000 people world wide lose their life to a virus that has been known about for over 4000 years. If more time and money were directed towards the efforts to find a cheap and effective treatment for rabies, tens of thousands of lives could be spared annually. ❁❁❁
Figure 1. This map shows the distribution of those countries that have a higher risk of their inhabitants getting the rabies virus.
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Figure 2. This representation of a rabies virus shows the structure and components present in all rabies viruses.
❁❁❁ Target Information: Promyelocytic leukemia (PML) protein is a protein that regulates transcription in both the nucleus and cytoplasm. PML also acts as a growth suppressor in cells. PML reside in structures called nuclear bodies. PML is also involved in the cell processes of cycle progression, DNA damage response, transcriptional regulation, viral infection, and apoptosis [2]. This protein is attacked by the rabies virus as the rabies’ P protein attaches to the C terminal of the PML protein which weakens the immune system as well as the defense against both DNA and RNA viruses.
Figure 3. This is a representation of a Promyelocytic leukemia protein. The protein is a beta sheet shown as ribbons.
❁❁❁ What do we know about the characteristics of the promyelocytic leukemia protein?
The promyelocytic leukemia protein has an average molecular mass of 97,551 g/mol.
PML is found in a eukaryotes cell's nucleus.
Promyelocytic leukemia proteins are found in all cells, and their function in a cell includes traveling from the nucleus to the cytoplasm in order to send information throughout the cell.
❁❁❁ Drug Information: Ribavirin is a guanosine analogue that fights against RNA and DNA diseases. The drug is taken orally and converts into ribavirin triphosphate (RTP) nucleoside monophosphate and diphosphate kinases. After the drug is converted, RTP is bound to the binding site of PNA polymerase. This binding of the two prevents the binding of the correct nucleotides. With the prevention of the binding, the drug forces the reduction of readings between the proteins. The main purpose of this drug is to inhibit proteins, such as promyelocytic leukemia, from replicated. The drug also prevents the binding of correct nucleotides in order to stop the replication of the protein [1].
Figure 4. This is a representation of the chemical make-up of Rabavirin. In this representation, oxygens are red, nitorgens are blue, and both hydrogens and carbons are grey.
❁❁❁ What are some characteristics of this drug?
The formula of ribavirin is: C8H12N4O5
The molecular weight is: 244.207 g/mol
The CAS number is: 36791-04-5
The most common delivery method of ribavirin is in the tablet form.
Some side effects of taking this drug include: headaches, fatigue, myalgia, and fever.
Other brand names for Ribavirin are Rebetol, Copegus, Ribasphere, RibaPak, Moderiba
The makerof this drug was Witkowski and his coworkers in 1972 [1]..
This drug is patented in both the United States and Canada.
This drug has had 758 clinical trials, and it was FDA approved in 1998, 26 years after its discovery.
The origin of this drug is human and veterinary therapy.
Alternatives to this drug is Taribavirin, an antiviral drug in its trial phase.
Some other miscellaneous facts about the drug is that it's a white, odorless drug that is soluble in water.
Ribavirin is also used as the main treatment for hepatitis C, but the drug used by itself is not effective enough to treat hepatitis C.
Motivation and Background:
Rabies is one of the most ancient known neurological diseases. The disease has been known for over 4000 years, but it was fatal with no treatment for most of that time. It was not until 1885 that the first vaccine for rabies was discovered. Rabies, although rare in the United States, account for about 55,000 deaths annually. Of the deaths, 1-3 of the cases are reported in the United States while the majority of the cases are from developing countries [6]. Rabies is a deadly virus that is contracted by humans through the bite of a mammal. In the United States, the most common transmitters of rabies are bats, coyotes, foxes, raccoons, and skunks [6]. Once the virus enters from the bite mark, the virus first interacts with the muscle cells. The virus replicates slowly and quietly while in the muscle cells so that the immune system does not attack the virus. After replicating in the muscle cells, the virus targets the phosphoprotein which decreases the gene that helps fight infectious diseases [2]. The ultimate effect of rabies is inflammation of the brain after an attack on the central nervous system. A rabies shot can be taken after an animal bite to try to prevent a rabies infection, but once the symptoms are present, other options must be considered. If no treatments are taken after these symptoms appear, the disease is fatal within days [6]. Although there are not many cases of rabies in the United States, 55,000 people world wide lose their life to a virus that has been known about for over 4000 years. If more time and money were directed towards the efforts to find a cheap and effective treatment for rabies, tens of thousands of lives could be spared annually.
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Target Information:
Promyelocytic leukemia (PML) protein is a protein that regulates transcription in both the nucleus and cytoplasm. PML also acts as a growth suppressor in cells. PML reside in structures called nuclear bodies. PML is also involved in the cell processes of cycle progression, DNA damage response, transcriptional regulation, viral infection, and apoptosis [2]. This protein is attacked by the rabies virus as the rabies’ P protein attaches to the C terminal of the PML protein which weakens the immune system as well as the defense against both DNA and RNA viruses.
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What do we know about the characteristics of the promyelocytic leukemia protein?
- The promyelocytic leukemia protein has an average molecular mass of 97,551 g/mol.
- PML is found in a eukaryotes cell's nucleus.
- Promyelocytic leukemia proteins are found in all cells, and their function in a cell includes traveling from the nucleus to the cytoplasm in order to send information throughout the cell.
❁❁❁Drug Information:
Ribavirin is a guanosine analogue that fights against RNA and DNA diseases. The drug is taken orally and converts into ribavirin triphosphate (RTP) nucleoside monophosphate and diphosphate kinases. After the drug is converted, RTP is bound to the binding site of PNA polymerase. This binding of the two prevents the binding of the correct nucleotides. With the prevention of the binding, the drug forces the reduction of readings between the proteins. The main purpose of this drug is to inhibit proteins, such as promyelocytic leukemia, from replicated. The drug also prevents the binding of correct nucleotides in order to stop the replication of the protein [1].
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What are some characteristics of this drug?
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References:
1. ribavirin | C8H12N4O5 - PubChem https://pubchem.ncbi.nlm.nih.gov/compound/ribavirin#section=Top (accessed Feb 5, 2017).
2. Scott, T.; Nel, L. Viruses 2016, 8 (8), 231
3. What are the signs and symptoms of rabies? https://www.cdc.gov/rabies/symptoms/index.html (accessed Feb 5, 2017).
External links:
1. https://www.cdc.gov/rabies/symptoms/index.html2. https://pubchem.ncbi.nlm.nih.gov/compound/ribavirin#section=Top
3. http://www.who.int/rabies/Global_distribution_risk_humans_contracting_rabies_2013.png?ua=1
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